Syk Inhibitors

Last updated on September 16, 2020 Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-in- development, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain health, as well as for age-related health concerns that can affect brain health (e.g., cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports include evaluation of safety data, from clinical trials if available, and from preclinical models. Syk Inhibitors Evidence Summary Syk inhibitors reduce immune cell activation and associated pathological inflammation, but so far clinical efficacy is limited to rare autoimmune diseases. Safety is good short-term, but long-term is unknown. Neuroprotective Benefit: Syk inhibition may protect against Aβ-mediated neuroinflammation and microglial dysfunction, as well as promote tau degradation, but more studies in human tissue are needed. Aging and related health concerns: Most efficacious in autoimmune diseases, but benefits are marginal. Limited effects as a monotherapy in hematological cancers, but may work in combination therapies. There are potential anti-fibrotic and senolytic effects. Safety: In clinical trials, the most common adverse effects were gastrointestinal issues, headache, and hypertension. The risk for infection is not significantly increased in the short term, but long-term safety has not been established. 1 Last updated on September 16, 2020 Availability: Rx or in clinical trials Dose: 100mg BID Oral Fostamatinib (for chronic ITP) Chemical formula: C23H26FN6O9P Half-life: 15 hours BBB: Not known MW: 580.5 g/mol Clinical trials: Phase 3 RCTs for Observational fostamatinib in autoimmune diseases ITP studies: None (n=76, n= 74) and RA (n=923, n=913, n=323). Phase 2 trials for fostamatinib, entospletinib, cerdulatinib, and mivavotinib in hematological malignancies. Source: PubChem What is it? Spleen tyrosine kinase (Syk) is a non-receptor tyrosine kinase, and is a member of the Src kinase family. It contains Src-homology 2 (SH2) domains which bind to phosphorylated immunoreceptor tyrosine- based activation motif (ITAM) sequences, leading to the recruitment and activation of additional adaptor proteins, leading to the induction of intracellular signaling cascades [1]. It is highly expressed in hematological cells, and plays important roles in B cell maturation, and immune cell signaling and activation. Consequently, clinical development for Syk inhibitors has focused on autoimmune diseases and hematological cancers. Two Syk inhibitors (fostamatinib and entospletinib) have undergone clinical testing, and two dual target receptors (cerdulatinib and mivavotinib) have been tested in clinical trials for cancer [2]. Fostamatinib is an oral Syk inhibitor that is marketed under the trade name Tavalisse® by Rigel Pharmaceuticals, and was licensed to Grifols for commercialization in Europe and Turkey. It was approved by the FDA in April 2018, and by the EMA in 2020 for chronic immune thrombocytopenia purpura, an autoimmune condition, in individuals with inadequate response to prior therapy. It has also been tested in clinical trials for rheumatoid arthritis, IgA nephropathy, autoimmune hemolytic anemia, and hematological malignancies. Development for cancer has been hampered by dose-limiting toxicities due to off-target kinase inhibition. Fostamatinib is a prodrug, which is cleaved to its active metabolite R406 by intestinal alkaline phosphatase [3]. Entospletinib (GS-9973) is a highly selective oral Syk inhibitor, with 14-fold selectivity for Syk over other kinases [4]. It is being developed by Gilead Sciences for hematological malignancies. 2 Last updated on September 16, 2020 Cerdulatinib is a dual Syk/JAK inhibitor being developed by Portola Pharmaceuticals (part of Alexion) primarily for hematological malignancies. Mivavotinib (TAK-659) is a dual Syk/Flt3 inhibitor being developed by Millennium/Takeda Oncology for hematological malignancies. Neuroprotective Benefit: Syk inhibition may protect against Aβ-mediated neuroinflammation and microglial dysfunction, as well as promote tau degradation, but more studies in human tissue are needed. Types of evidence: • Numerous laboratory studies Human research to suggest prevention of dementia, prevention of decline, or improved cognitive function? None Human research to suggest benefits to patients with dementia: None Mechanisms of action for neuroprotection identified from laboratory and clinical research: Alzheimer’s disease: POTENTIAL BENEFIT (Preclinical) Syk is implicated in the microglial dysfunction that promotes neuroinflammation and facilitates tau propagation in the context of Alzheimer’s disease (AD). In preclinical AD models, Syk inhibitors exhibit neuroprotection by reducing pathogenic neuroinflammation. In a study of changes in gene expression networks within the hippocampus across the lifespan, Syk was found to be part of a dysregulated gene network that was elevated with aging, and the effect was exacerbated in the context of AD [5]. Although there is evidence for pathological Syk activation in the human AD brain, species or disease- related differences in Syk processing and localization calls into question whether Syk inhibitors would offer similar therapeutic benefit in humans. Tau pathology: In rodent AD models, Syk activation is present in a subset of microglia and Aβ-plaque associated dystrophic neurites [6; 7; 8]. Neurons with activated Syk had tau accumulation. Although, studies in rodents and cell culture suggest that Syk can facilitate tau phosphorylation, it appears not to be a major contributor to tau phosphorylation in the human hippocampus [7]. In postmortem AD brain tissue from the dorsolateral prefrontal cortex, activated Syk was detected in dystrophic neurites around 3 Last updated on September 16, 2020 Aβ plaques and in tau containing neurons [8]. A separate study examining postmortem AD brain tissue from the hippocampus did not see a clear association of activated Syk with dystrophic neurites, but rather, Syk was primarily localized to stress granules and granulovacuolar degeneration (GVD) inclusions, which are associated with disturbed autophagy [7]. Microglia exposed to Aβ form stress granules, and Syk enhances the formation of stress granules [9]. Within the stress granules, activated Syk stimulates the production of neurotoxic reactive oxygen species (ROS) and reactive nitrogen species (RNS). The sequestration of Syk into the granules may be a neuroprotective response aimed at facilitating Syk clearance, but defective autophagic clearance may lead to the accumulation of Syk containing cytoplasmic aggregates [7]. In a rodent tauopathy model (Tau P301S), Syk inhibition (via BAY61-3606) promotes autophagic tau degradation, by inhibiting the Akt/mTOR pathway [10]. It is unclear whether the presence of activated Syk within cytoplasmic aggregates in the AD brain contributes to the defect in their clearance by autophagy. Within microglia, the sequestration of Syk within stress granules impairs phagocytic capacity, including Aβ uptake, in cell culture, and re-localization of Syk from the cytoplasm to the plasma membrane restores phagocytosis in these cells [9]. Phagocytosis: Syk is essential for phagocytosis in macrophages and microglia [9]. Many phagocytic receptors are associated with proteins with ITAM domains. The phosphorylation of the ITAM domains leads to the recruitment of Syk, which then initiates various intracellular signaling cascades, including those associated with phagocytosis. TREM2 mediated phagocytosis in microglia involves Syk activation and signaling through the P13K/Akt/PLCγ pathways [11]. In AD models, a TREM2 activating antibody activated Syk signaling and promoted phagocytic clearance of Aβ [12]. Therefore, Syk inhibition would be expected to impair the therapeutic efficacy of TREM activating antibodies. Neuroinflammation: Syk plays multiple roles in microglia, which may have opposing impacts on AD- related pathology. Syk can promote phagocytic clearance, but it can also promote the secretion of proinflammatory cytokines. The outcome is likely determined by the composition of ITAM containing receptor complexes within a given cellular environment, and thus subject to conditional context. Syk is a downstream mediator of TREM2-related phagocytosis, but it does not participate in the anti- inflammatory effects of TREM2 [11]. In the absence of TREM2/DAP12, Syk activation primarily has a proinflammatory effect. This suggests that dysregulation of TREM2 or other Syk interacting proteins may drive a pathological dysregulation of Syk in AD. In organotypic brain slices from an AD model (Tau P301S), proinflammatory cytokine levels were elevated relative to wild type, including a 3 fold increase in IL-1β and 1.5 fold increase in IL-6, and these increases could be alleviated by Syk inhibition [6]. The increase in these cytokines in response to elevated Syk may derive from the essential role of Syk in activation of the NLRP3 inflammasome. Syk activation is also associated with the activation of NF-kB, 4 Last updated on September 16, 2020 and in an AD mouse model (Tg19959), treatment with a Syk inhibitor (BAY61-3606) improved spatial memory, based on performance on the Morris water maze, and was neuroprotective against NF-kB associated neuronal loss [13]. Overall,

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